ABSTRACT Global HIV-1/AIDS prevention efforts have been greatly facilitated by the demonstration that anti-retroviral drugs (ARVs) for pre-exposure prophylaxis (PrEP) and treatment as prevention can be effective in preventing the spread of HIV-1. However, the challenges of achieving high adherence, the cost of implementation, and potential for future changes in ARV drug resistance patterns underscore the continuing need for new approaches to HIV- 1 prevention. In particular, novel interventions that target host immune responses may be less likely to elicit viral escape, and may enhance host responses to future HIV-1 prevention vaccines. Genital tract inflammation is known to be associated with altered risk of HIV-1 acquisition. Studies have reported that inflammatory responses to sexually transmitted infections (STI), the presence of genital tract inflammatory cytokines (e.g., IL-7, TNF-?, and IL12p70), chemokines (e.g., CCL7, and CXCL9), and cellular immune activation are associated with increased risk of HIV-1 infection. One explanation for these observations is that these inflammatory environments result in the accumulation of activated immune effector cells, which increase available targets for HIV-1 infection. However, studies of Kenyan female sex workers have found that natural host resistance to HIV-1 infection is associated with lower levels of immune activation (e.g., ?immune quiescence?). This reduced immune activation did not reflect a state of broad immunosuppression insofar as these women had otherwise normal host responses to exogenous antigens. This suggests that intrinsic host pathways may regulate genital tract inflammatory responses, and these regulatory mechanisms may alter the risk of HIV-1 infection. However, studies also report that, in some settings, immune activation may be associated with reduced HIV-1 acquisition, raising the caution that use of interventions to broadly induce nonspecific immunosuppression could have unintended effects, such as eliminating effective barriers to HIV-1 or to defenses against other co-infections. The public health challenge is to identify genital tract inflammatory pathway(s) that can mitigate risk of HIV-1 acquisition without increasing risk of other infections. We recently documented the presence of variants in two genes, CD101 and UBE2V1, which are strongly associated with altered HIV-1 infection risk. Both of these genes have been previously reported to have roles in regulating host inflammatory responses. Given these genetic associations with HIV-1 acquisition risk, and a priori evidence that these genes may modify host inflammatory responses, we hypothesize that these genes may modulate HIV-1 acquisition risk through altering underlying host inflammatory responses in the genital tract. Here we propose molecular and epidemiologic studies to evaluate the association of these gene variants with inflammation of the female genital tract.